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Agile Mind's core product—a comprehensive on-line instructional platform—supports student engagement and achievement in middle- and high-school mathematics and science. With IES SBIR funding, Agile Mind developed 30 web-based visualizations to embed in the biology modules of its core product. These interactive and animated visualizations address concepts central to state and national standards. Key features of the visualizations include: (a) elements a user manipulates (start/pause/repeat buttons, sliders, drag-able pieces, variables to adjust); (b) imagery that explicitly makes real-world connections to key conceptual content; (c) multiple representations to support deeper understanding of concepts (graphical depictions, caption narratives, tables of data from observed phenomena); and (d) automated and customized feedback from the software to student to support learning. The visualizations provide opportunities for discovery-based learning from real-world biology examples that ordinarily would not be possible in classroom settings.
The animations and simulations in the visualizations were iteratively developed by Agile Mind with feedback from education experts, teachers, and students. Development began with a storyboard, which was then converted into functional specifications for the animation by an instructional designer. After review by beta testers, animators and programmers created art for the storyboard, bringing to life the pedagogical intent of the authors. The pieces were checked again to ensure accuracy and functionality. The final visualizations were incorporated into Agile Mind Biology, where the visualizations are viewed and played as part of the course content. An animation player automatically captures information about how students interact with the visualizations. These data are used by the developers to continually refine and improve the visualizations.
A mixed-methods study was completed with 19 teachers and 312 9th and 10th grade students from eight schools in two states. All students in this study received the intervention as a supplement to regular instruction for three to four months. The study examined feasibility and usability of the visualizations, and the potential of the visualizations to support student engagement and learning of biology content. The research team also explored visualization design features, amount and context of use, and the utilization of various instructional strategies. Students were more engaged in content that was supplemented by visualizations than content that did not have an accompanying visualization, and students who used the visualizations for longer periods of time had greater self-reported understanding of science concepts than students who used the visualizations for shorter periods of time. Visualizations appear to be most effective when integrated within challenging standards-centered lessons because they facilitate inquiry learning that would otherwise have not been possible. The research team plans to test the efficacy of the visualizations to improve student learning in future work.
Path to Commercialization:
Founded in 2002, Agile Mind is a technology company dedicated to broadening student access, achievement, and persistence in challenging, contemporary mathematics and science courses, and to fostering exemplary, sustainable teaching practices. The visualizations developed through IES SBIR funds and the 250 additional visualizations developed after the project ended (which are based on the IES-funded R&D) have been commercialized. In addition, Agile Mind now has direct licenses of the Biology course program with schools and districts in 9 states. At present, thousands of educators and more than 90,000 students have used these visualizations. Fees from education entities licensing Agile Mind programs and services (including Biology visualizations) provide 85 percent of the company's operating capital.


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Michael's Memorial Service
Videos of the Service, Tributes and Memories »
We will celebrate Michael's life on Sunday, August 21, at 1:00pm at The Glaser Center in Santa Rosa. The address is 547 Mendocino Ave, Santa Rosa, CA. Light refreshments will be served after the memorial. All are welcome.
It is not necessary, but I would appreciate it if you would let me know if you think you will be coming so I can get an idea of numbers – best way is to email me directly at firstname.lastname@example.com.
Directions and parking information here.
Parting Thoughts: My Home on the Web
This is a very personal website. It is my place to tell stories and pass along my view of the world, for my family, friends, and anyone else who is interested.
I am currently fighting cancer of the intestine, and it doesn't look like I have a lot of time left. This website will, I hope, outlive me by many years and project a bit of me into the future.

subset: commoncrawl


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Lukenya Notes: Taking CLTS to Scale with Quality
The Lukenya Notes are a collection of experiences and key recommendations from the IDS meeting of CLTS practitioners held in Lukenya, Nairobi in July 2011, immediately after the AfricaSan3 meeting. The aim of the workshop was to focus on the key challenges we all face in taking CLTS to scale. Insights, case studies and options are clustered by themes which emerged from workshop brainstorming.


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Investors are still pouring millions into scooter startups, albeit sometimes at flat valuations. At the same time a little cash is flowing the other way, in cases where cities have realized the importance of prioritizing the needs of the local environment and its citizens, over and above the ambitions of VCs for a swift and lucrative exit.
Scooter startups affected by such regulatory bumps in the road are, unsurprisingly, rather less keen to shout about this sort of policy friction and the negative cash and ride flow it generates.
In one recent incident in Spain, in the Catalan capital of Barcelona, El Pais reported that the town hall fined a local scooter startup, called Reby, for contravening urban mobility rules.
The startup is so new it doesn't even have scooters available for public hire yet. But it's already had some of its 'test' rides removed by police and been fined for breaking scooter sharing rules.
If it was hoping to copy-paste from an Uber 1.0 playbook, things aren't looking good for Reby. (Indeed, that's a very tatty manual in most places these days.)
Spain's capital city Madrid also forced a temporary suspension on scooter sharing startups recently, as we reported last month, after changes to mobility laws that tighten the screw on scooter sharing — requiring already operational startups to tweak how their rides operate in order to come into compliance.
While Madrid authorities haven't banned scooter sharing entirely, they have imposed more limits on where and how they can be used, thereby injecting fresh friction into the business model.
But compared to Barcelona that's actually a free ride. Things aren't so much bumpy as roadblocked entirely for scooter sharing in the latter city where regulations adopted by Barcelona town hall in 2017 essentially ban the on-demand scooter model, at least as startups prefer to operate it.
These rules require companies that wanting to offer scooters for hire must provide a guide with the ride (one guide per maximum two people), as well as a helmet. They must also verify that the person to whom the vehicle is hired has the ability to ride it properly.
Rides might scale if you're able to litter enough cheap and easy scooters all over the urban place but a (human) guide per two rides definitely does not.
Yet, as we've written before, there's no shortage of patinetes electronics weaving around Barcelona's often narrow and crowded streets. Most of these are locally owned though. And the town hall appears to prefer it that way. After all, people who own high tech scooters aren't usually in a rush to ditch them in stupid places.
In its 2017 by-law regulating various personal mobility vehicles (PMVs) — including, but not limited to, two-wheeled electric scooters — the city council said it wanted to foster safer and sustainable usage of scooters and other PMVs, pointing to "the growing presence of this new mobility which is taking up more and more road space".
"Barcelona City Council is committed to a sustainable city mobility model which gives priority to journeys on foot, by bicycle or on public transport," it added, setting out what it dubbed a "pioneering regulation" that forbids e-scooter use on pavements; imposes various speed restrictions; and gives priority to pedestrians at all times.
Scooters can also only be parked in authorized parking places, with the council emphasizing: "It is forbidden to tie them to trees, traffic lights, benches or other items of urban furniture when this could affect their use or intended purpose; in front of loading or unloading zones, or in places reserved for other users, such as persons with reduced mobility; in service areas or where parking is prohibited, such as emergency exits, hospitals, clinics or health centres, Bicing [the local city bike hire scheme] zones and on pavements where this might block the path of pedestrians."
There's more though: The regulation also targets scooter sharing startups seeking to exploit PMVs as a commercial opportunity — with "special conditions for economic activities".
These include the aforementioned guide, helmet and minimum skill level rule. There's also a registration scheme for PMVs being used for economic activity which allows city police to scan a QR code that must be displayed on the ride to check it conforms to the regulation's technical requirements. How's that for a smart use of tech?
"There may be specific restrictions in specific areas and districts where there is a lot of pressure from these kinds of vehicles or they pose a specific problem," the council also warns, giving itself further leeway to control PMVs and ensure they don't become a concentrated nuisance.
Despite what are clear, strict and freshly imposed controls on scooter sharing, that hasn't stopped a couple of smaller European startups from trying their luck at getting rentable rubber on Catalan carrers anyway — perhaps encouraged by demonstrable local appetite to scoot (that and the lack of any big Birds).
The opportunity probably looks tantalizing; a dense urban environment that's also a tourist hotspot with clement weather, lots of two-wheel-loving locals and a small but vibrant tech scene.
In Reby's case, the very early stage Catalan startup, whose co-founders' LinkedIn profiles suggests the business was founded last July, has a website and not much else at this point, aside from its ambitions to follow in the wheeltracks of Bird, Lime et al.
Nonetheless it has racked up fines worth €5,300 (just over $6,000), according to town hall sources, after being deemed to have breached the city's PMV rules.
Reby had put out up to a hundred scooters in Barcelona for ten days, according to El Pais, padlocking them to bike anchors (with a digital password for unchaining delivered via app) — presumably in the hopes of locating a grey area in the regulation and unlocking the pile em' high, rent em' cheap dockless on-demand scooter model that's disrupted cities elsewhere.
But the Ayuntamiento de Barcelona was unimpressed. Its new by-law brought in a penalty system with fines of up to €100 for minor infringements, up to €200 for serious infringements and up to €500 for very serious infringements. (We understand Reby received 53 sanctions for minor infringements — costing €100 apiece).
Penalties are levied per infringement, so essentially per scooter deployed on the street. And while a few thousand euros might not sound that much of a big deal, the more scooters you scatter the higher the fine scales. And of course that's not the kind of scaling these startups are scooting for.
We asked Reby for its version of events but it didn't want to talk about it. A spokesman told us it's still very early days for the business, adding: "We are a very small team and haven't launched yet officially. We are doing some tests in Barcelona."
A more established European scooter startup, Berlin-based Wind, has also clashed with city hall. El Pais reports it had around 100 scooters seized by police last August, also after abortively trying to put them on the streets for hire.
Town hall sources told us that, in Wind's case, the company's rides were removed immediately by police, not even lasting a day — so there wasn't even the chance for a fine to be issued. (We contacted Wind for comment on the incident but it did not respond.)
The bottom line is legislative hurdles won't simply vanish because startups wish it.
Where scooters are concerned city authorities aren't dumb and can also move surprisingly fast. The dumping grounds some urban spaces have become after being flooded with unwanted dockless rides by overfunded startups chasing scale via max disruption (and minimum environmental sensitivity) certainly hasn't gone unnoticed.
At the same time, keeping streets flowing, uncluttered and safe is the bread and butter business of city councils — naturally pushing PMVs up the regulatory agenda.
You also don't have to look far for tragic stories vis-a-vis scooters. Last summer a 90-year-old pedestrian was killed in a suburb of Barcelona after she was hit by two men riding an electric scooter. In another incident in a nearby town a 40-year-old scooter rider also reportedly died after falling off her ride and being run over by a truck.
The risks of PMVs mingling with pedestrians and more powerful road vehicles are both clear and also not about to disappear. Not without radical action to expel most non-PMV vehicles from city centers to expand the safe (road) spaces where lower powered, lighter weight PMVs could operate. (And no major cities are proposing anything like that yet).
Add to that, in European cities like Barcelona, where there has already been major investment in public transport infrastructure, there's a clear incentive to funnel residents along existing tracks, including by tightly controlling new and supplementary forms of micro-mobility.
If the Barcelona city council has one potential blind spot where urban mobility is concerned it's air pollution. Like most dense urban centers the city often suffers terribly from this. And savvy scooter companies would do well to be pressing on that policy front.
But there's little doubt that would-be fast-follower scooter clones have their work cut out to scale at all, let alone go the distance and get big enough to attract acquisitive attention from the category's beefed up early movers.
Even then, for the Birds and Limes of the scooter world, multi-millions in funding may buy runway and the opportunity to scoot for international growth but policy roadblocks aren't the kind of thing that money alone can shift.
Scooter startups need to sell cities on the potential civic benefits of their technology, by demonstrating how PMVs could replace dirtier alternatives that are already clogging roads and having a deleterious impact on urban air quality, as part of a modern and accessible mobility mix.
But that kind of lobbying, while undoubtedly benefiting from local connections, takes money and time. So there's no shortage of challenge and complexity in the road ahead for scooter startups, even as — as we wrote last month — the investment opportunity is shrinking, with investors having now placed their big bets.
In some cities, scooter ownership also appears to be growing in popularity which will also eat into any sharing opportunities.
One regional investor from an early stage Madrid-based fund that we spoke to about scooters had no qualms at having passed over the space. "We've looked at various companies in the space and in Spain but we're not very attracted by the market given our fund size, competition and regulation question marks," KFund's Jamie Novoa told us.
So those entrepreneurs still dreaming of fast following the likes of Bird, Lime and Spin may find the race they were hoping to join is already over and park gates being padlocked shut.


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Chinese noodle making is so resourceful, the operating principle seems to be, "If you can turn it into flour, it can be a noodle." Chinese cooks recognize the noodle's value as a cheap, portable, non-perishable foodstuff, and large-scale commercial production was underway as early as 100 AD. Because of its long shape, it gained cultural status as the icon for longevity. To this day, noodles are requisite at birthday parties.
Chinese rice noodles are the precursor of the rice sticks or noodles (included in the recipe for Kway'teo on page 10) of Thai cuisine, and Chinese mung bean noodles gave birth to the cellophane noodles of Vietnam.
Japanese noodles also trace their origins to China. Udon, a thick Japanese noodle typically made from wheat, is served hot in soups or cold with a dipping sauce. Other notable Japanese noodles include the buckwheat noodle, Soba, and the thin wheat noodle called Somen. Oh, and a newsflash for college students who live on them: In a millennial survey of what Japanese people considered their most influential contribution to 20th-century life, Instant Ramen topped the list-ahead of karaoke, headphones, video games and compact discs.
Charming as it may be, the story that Marco Polo introduced noodles to Italy on his return from China is fiction. Numerous sources point to early noodle-like foods eaten outside of China, including a discussion in the 5th-century Jerusalem Talmud about whether boiled dough could be considered unleavened bread under Jewish dietary laws.
—By Jo Marshall


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Here's 'The Situation' -- Dude Was a Stripper
Here's 'The Situation' Dude Was a Stripper
Before "The Situation" took his shirt off on "Jersey Shore" -- dude used to take his pants off for anyone willing to shove a dollar in his banana hammock.
TMZ has learned The Situation -- aka Mike Sorrentino -- was a member of the "All American Male" exotic dancer crew back before his reality show days.
We're told The Situation worked for the group -- which gyrates from New York to New Jersey -- back in 2004.
These photos were taken at a bachelorette party -- we're told The Sitch gave a "great lap dance."


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I spend all summer fantasizing about winter. From the end of May to the beginning of October, I wind up drenched in sweat, wishing I could peel off my own skin and running from one air conditioned environment to another. It's miserable. When the biting cold of the winter season hits, I embrace it, finally able to be somewhat comfortable when I'm outside. Add a bit of snow to the equation, and the result is positively heavenly.
So, when I saw The Weather Channel's list of snowiest cities in the United States, my mind immediately wandered to chilly places where I could hop on a sled (which I prefer to skis or snowboards), pour a big, steaming mug of hot chocolate and hurl snowballs at random passers by.
Are you into that sort of thing? Well, you'll probably want to dash off to one of the 10 snowiest cities in the country! In case you're wondering, here they are:
%Gallery-108139%1. Valdez, Alaska: The Weather Channel reports that this city gets 297.7 inches of snow a year, with 180 of them coming in only one month. If you go to the second snowiest city in the country, the annual average is six feet lower than it is in Valdez. Slackers.
2. Boonville, New York: Boonville just sounds like a snowy place. With 220.5 inches a year, this town in the foothills of the Adirondacks calls itself the "Snow Capital of the East" and has the powder to back up that claim.
3. Hancock, Michigan: In December, 56 inches of snow are dumped on Hancock, with another 68 inches following in January. The city averages 218 inches a year and once boasted of two feet of wet snow on June 2. This is my kind of place!
4. Crested Butte, Colorado: From November through March, you can expect at least 30 inches of snow to fall every month, with an annual average of 217.7 inches. If you like snow to shroud your Labor Day barbecue, this is the place to be – you can also find snow falling as late as the end of June.
5. Truckee, California: In the late 1800s, one storm pummeled Truckee with 10 feet of snow over two days. Since then, the elements have been merciful, if you call an annual average snowfall of 198.3 inches merciful. Do the math on this one.
6. Lead, South Dakota: Storms dropping more than 10 inches of snow hit at least three times a year in this city, which averages 187 inches of snow a year.
7. Steamboat Springs, Colorado: For 97 days a year, you can expect this mile-high city to have at least 10 inches of snow on the ground. The annual average snowfall of 175.5 inches is nothing to sneeze at.
8. Red Lodge, Montana: There have been years where snow didn't fall in only two months – that's what it takes to score an annual average of 173.9 inches. And, the snow lingers: there's at least an inch on the ground 127 days a year.
9. Tahoe City, California: The snow doesn't start to fall until November, but when it does, it comes plentifully. Tahoe City averages 170.8 inches a year.
10. Ironwood, Michigan: This city has a slightly pornographic name and a hell of a lot of snow. Ironwood averages 164.6 inches of snow a year and is a hot spot for winter sports, according to The Weather Channel.
[photo by bsabarnowl via Flickr]


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The World Health Organization (WHO) has called for the "virtual elimination" of pediatric HIV: a mother-to-child HIV transmission (MTCT) risk of less than 5%. We investigated uptake of prevention of MTCT (PMTCT) services, infant feeding recommendations, and specific drug regimens necessary to achieve this goal in Zimbabwe.
Methods and Findings
We used a computer model to simulate a cohort of HIV-infected, pregnant/breastfeeding women (mean age, 24 y; mean CD4, 451/µl; breastfeeding duration, 12 mo). Three PMTCT regimens were evaluated: (1) single-dose nevirapine (sdNVP), (2) WHO 2010 guidelines' "Option A" (zidovudine in pregnancy, infant nevirapine throughout breastfeeding for women without advanced disease, lifelong combination antiretroviral therapy for women with advanced disease), and (3) WHO "Option B" (pregnancy/breastfeeding-limited combination antiretroviral drug regimens without advanced disease; lifelong antiretroviral therapy with advanced disease). We examined four levels of PMTCT uptake (proportion of pregnant women accessing and adhering to PMTCT services): reported rates in 2008 and 2009 (36% and 56%, respectively) and target goals in 2008 and 2009 (80% and 95%, respectively). The primary model outcome was MTCT risk at weaning.
The 2008 sdNVP-based National PMTCT Program led to a projected 12-mo MTCT risk of 20.3%. Improved uptake in 2009 reduced projected risk to 18.0%. If sdNVP were replaced by more effective regimens, with 2009 (56%) uptake, estimated MTCT risk would be 14.4% (Option A) or 13.4% (Option B). Even with 95% uptake of Option A or B, projected transmission risks (6.1%–7.7%) would exceed the WHO goal of less than 5%. Only if the lowest published transmission risks were used for each drug regimen, or breastfeeding duration were shortened, would MTCT risks at 95% uptake fall below 5%.
Citation: Ciaranello AL, Perez F, Keatinge J, Park J-E, Engelsmann B, Maruva M, et al. (2012) What Will It Take to Eliminate Pediatric HIV? Reaching WHO Target Rates of Mother-to-Child HIV Transmission in Zimbabwe: A Model-Based Analysis. PLoS Med 9(1): e1001156. https://doi.org/10.1371/journal.pmed.1001156
Academic Editor: Agnes Binagwaho, Rwanda Ministry of Health, Rwanda
Received: February 27, 2011; Accepted: November 29, 2011; Published: January 10, 2012
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: Funding for this work was provided by the Elizabeth Glaser Pediatric AIDS Foundation (all authors) and the National Institute of Allergy and Infectious Disease (K01 AI078754 [ALC], K24 AI062476 [KAF], R01 AI058736 [KAF, RPW, JC, JP]). The funders had no role in study design, interpretation of results, or decision to publish.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: ANC, antenatal care; ART, antiretroviral therapy; ARV, antiretroviral drug; CEPAC, Cost-Effectiveness of Preventing AIDS Complications; MTCT, mother-to-child HIV transmission; NVP, nevirapine; PMTCT, prevention of mother-to-child HIV transmission; POP, product of participation; SD, standard deviation; sdNVP, single-dose nevirapine; WHO, World Health Organization; ZDV, zidovudine
Editors' Summary
A woman who is infected with HIV can pass the virus to her baby during pregnancy, labor and delivery, or breastfeeding—mother-to-child HIV transmission (MTCT). Without treatment, up to 30% of babies born to HIV-infected women will become infected with HIV during pregnancy or at delivery, and a further 5%–20% will become infected through breastfeeding. In 2009, around 400,000 children under 15 years of age became infected with HIV, mainly through MTCT—90% of these MTCT infections occurred in Africa.
In addition to preventing HIV infection among prospective parents and avoiding unwanted pregnancies among HIV-positive women, effective prevention of MTCT (PMTCT) requires preventing the transmission of HIV from infected mothers to their infants during pregnancy, labor, delivery, and breastfeeding.
In 2010, the World Health Organization (WHO) published new guidelines for PMTCT based on combination antiretroviral therapy for women with advanced HIV disease, and two options for countries to select for women with less advanced disease. Option A includes zidovudine (ZDV) during pregnancy and single-dose nevirapine (sdNVP) at delivery, followed by daily nevirapine syrup for infants throughout the duration of breastfeeding; Option B includes maternal triple-drug ARV regimens throughout pregnancy and breastfeeding. However, WHO estimates that only 53% of pregnant women worldwide received any antiretroviral medicines for PMTCT in 2009.
Why Was This Study Done?
As in many sub-Saharan African countries where prolonged breastfeeding is common, and necessary to improve child health, Zimbabwe is implementing the 2010 WHO guidelines with Option A. However, because of the challenges of enrolling and retaining women in PMTCT programs, the effectiveness of this strategy is unknown. Therefore in this study, the researchers used a model to calculate the level of PMTCT uptake in Zimbabwe, the PMTCT drug regimens, and the duration of breastfeeding that would be necessary to reach the WHO goal of an MTCT risk below 5%.
What Did the Researchers Do and Find?
The researchers used a validated computer simulation model developed for analyzing the cost-effectiveness of preventing AIDS complications to measure risk of infant HIV transmission at the time of weaning, the HIV infection risk at 4–6 weeks of age, infant survival at two years of age, and 2-year HIV-free survival. The researchers used four scenarios of PMTCT uptake and linked the models to two populations of pregnant and breastfeeding women (mean age, 24 years) in Zimbabwe, and then analyzed the combinations of the factors necessary to reach MTCT risks less than 5%.
At baseline, the researchers found that the 2008 National PMTCT Program in Zimbabwe led to a projected 12-month MTCT risk of 20.3%. The projected risk in 2009 was 18.0% because of improved uptake. The estimated MTCT risk with Option A at 56% uptake (2009 levels) was 14.4% and with Option B was 13.4%. However, even with greatly increased uptake, such as 95% levels, the researchers found that projected transmission risks would exceed the WHO goal of less than 5% MTCT, and that the MTCT risk would fall below 5% at the 95% uptake level only if the lowest transmission risks were used for each drug regimen, or if breastfeeding duration were shortened.
What Do These Findings Mean?
These findings show that the planned implementation of the 2010 WHO PMTCT guidelines with Option A in Zimbabwe could substantially reduce infant HIV infection risk compared to the 2009 national program with sdNVP. Furthermore, in order to reach a MTCT risk of less than 5%, a national program based on either Option A or Option B will also need to include strategies to improve access to PMTCT services (to almost 100% uptake), retain women in care, and support medication adherence throughout pregnancy and breastfeeding. These findings from a resource-limited country with high HIV prevalence and prolonged breastfeeding may be useful for other countries in sub-Saharan Africa.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001156.
- Avert gives some more information on MTCT and PMTCT.
- The United Nations Children's Fund has factsheets on national PMTCT responses in the most affected countries.
- WHO's strategic vision for PMTCT for 2010–2015 is also available.
When antiretroviral drugs (ARVs) are administered during pregnancy, and breastfeeding is avoided, mother-to-child HIV transmission (MTCT) may occur in fewer than 1% of pregnancies [1]. These highly effective prevention strategies have led the pediatric HIV epidemic to be nearly eliminated in the United States and Europe [1],[2]. In settings where breastfeeding is recommended for improved infant health [3], recent trials have demonstrated that the provision of ARVs to breastfeeding mothers or their infants can reduce total MTCT rates to 1%–5% at 6 mo of age [4]–[15]. Based on these encouraging results, in 2009, HIV prevention and treatment organizations emphasized a new goal: the "virtual elimination" of pediatric HIV infection, defined as the reduction of MTCT to less than 5% [16]–[20]. Toward this goal, the World Health Organization (WHO) released new guidelines for the prevention of MTCT (PMTCT) in 2010, based on combination antiretroviral therapy (ART) for women with advanced HIV disease, and country-level selection between two antiretroviral options during pregnancy and breastfeeding ("Option A" or "Option B") for women with less advanced disease [21]. Option A includes zidovudine (ZDV) during pregnancy and single-dose nevirapine (sdNVP) at delivery, followed by daily nevirapine (NVP) syrup for infants throughout the duration of breastfeeding; Option B includes maternal triple-drug ARV regimens throughout pregnancy and breastfeeding (Table A in Text S1) [21].
However, opportunities for PMTCT may be lost at each step in a "cascade" of care, from presentation to antenatal care (ANC), through HIV testing and result receipt, to ARV adherence through the many months of pregnancy and breastfeeding (Figure 1; Figure A in Text S1 [22]–[25]. The WHO estimates that only 53% of pregnant women worldwide received any ARVs for PMTCT in 2009 [19]. As a result, more than 370,000 new perinatal HIV infections were estimated to have occurred in 2009; the majority of these were in sub-Saharan Africa, where access to pediatric HIV therapy is limited and infant mortality is extremely high [19],[26].
This figure shows the "two dimensions" in which PMTCT services can be improved. First, along the vertical arrow, PMTCT programs can transition to more intensive drug regimens (i.e., from sdNVP to Option A to Option B). Second, along the horizontal arrow, programs can undertake interventions to improve "uptake" of PMTCT services, defined as the proportion of pregnant, HIV-infected women who receive and adhere to ARVs for PMTCT, for example, from 36% in 2008 to 56% in 2009, and perhaps to 80% or 95% with future scale-up effort. Within the horizontal arrow are depicted the three "domains" of uptake examined in these analyses: care and testing, drug availability, or retention. sdNVP represents the current National PMTCT Program, based largely on sdNVP; "Option A" and "Option B" are the WHO 2010 PMTCT guideline-recommended regimens, as defined in the text and Text S1.
Since 2002, the Zimbabwean national PMTCT program has provided ART to pregnant women with clinical evidence of WHO stage 3/4 disease, and sdNVP to all others [27]. As in many sub-Saharan African countries where prolonged breastfeeding is common, Zimbabwe is implementing the 2010 WHO guidelines with Option A. Because of the challenges of enrolling and retaining women in care at each step in the PMTCT cascade, it is not known how effective this strategy will be. We used a simulation model to project the level of PMTCT uptake in Zimbabwe, the PMTCT drug regimens, and the duration of breastfeeding that would be necessary to reach the WHO "virtual elimination" goal of an MTCT risk below 5%.
Analytic Overview
We expanded a validated computer simulation model of MTCT [28],[29] to include each step in the "cascade" of PMTCT-related care, from first presentation at ANC through 2 y postpartum (Figure A in Text S1). The MTCT model simulates a single pregnancy, delivery, and postpartum period for each mother–infant pair, and projects infant outcomes at birth. Additional clinical events for mothers and infants through 2 y after delivery are simulated using the CEPAC (Cost-Effectiveness of Preventing AIDS Complications) model (Figure B in Text S1) [30]–[32]. The primary outcome of the linked CEPAC and MTCT models is risk of infant HIV transmission at the time of weaning; secondary outcomes include HIV infection risk at 4–6 wk of age, 2-y pediatric survival, and 2-y HIV-free pediatric survival.
This analysis examined improvements along two dimensions of PMTCT care: more effective PMTCT regimens, and improved uptake of the PMTCT "cascade" (Figure 1). We examined three possible PMTCT regimens in Zimbabwe: (1) the 2002–2009 National PMTCT Program, based on sdNVP alone, (2) WHO 2010 guidelines' Option A, and (3) WHO 2010 guidelines' Option B. Infant outcomes were projected at four levels of PMTCT uptake (36%, 56%, 90%, and 95% of women/infants receiving medications by the time of infant delivery) [19],[23]. Key sensitivity analyses examined the impacts of duration of breastfeeding, maternal HIV disease stage, the range of published MTCT risks for each PMTCT regimen, and a "full" (100%) uptake scenario.
The linked models were used to simulate two populations of pregnant and breastfeeding women in Zimbabwe, with mean age of 24 y (standard deviation [SD]: 5 y) [33]. Cohort 1 included women already HIV-infected at their first ANC visit (regardless of whether HIV status was known to patients or providers). Cohort 2 was composed of all women becoming pregnant each year in Zimbabwe, an estimated 392,460 women [34],[35], with HIV prevalence of 16% at first ANC visit and HIV incidence of 1%/year during late pregnancy and breastfeeding [36]. Cohort 1 was thus nested within Cohort 2. Cohort 1 was analyzed to project MTCT rates, and Cohort 2 to project the proportion and number of infants in an annual birth cohort anticipated to become HIV-infected by 18 mo of age. All women were assumed to breastfeed their infants for 12 mo in the base case, based on WHO infant feeding guidelines [3].
PMTCT Regimens and PMTCT Uptake Scenarios
The antenatal, intrapartum, and postpartum/neonatal components of each modeled PMTCT regimen are detailed in Table A in Text S1. In all modeled regimens, women identified as eligible for ART (CD4≤350/µl or WHO stage 3/4 disease) were referred for ART. The availability of ART after referral depended on the modeled PMTCT uptake scenario; the availability of CD4 assays was varied in sensitivity analyses. Following convention, we refer to combination antiretroviral therapy regimens as "ART" when intended for treatment of maternal HIV disease (also effective for PMTCT) and as "triple-drug ARV regimens" when offered to non-ART-eligible women for PMTCT.
To create the four uptake scenarios, the "cascade" of PMTCT services was categorized into three broad domains (Table 1; Figure 1): "care and testing," "drug availability," and "retention." We then calculated a "product of participation" (POP), defined as the product of the proportions of women/infants receiving care in each of these three domains, both at delivery and at the end of the breastfeeding period [23]. Four primary scenarios of PMTCT uptake were simulated for each PMTCT regimen (Table 1). The first two scenarios reflected WHO and Zimbabwean Ministry of Health and Child Welfare estimates of uptake at each step in the PMTCT cascade for Zimbabwe in 2008 (total POP at delivery: 36%) and 2009 (total POP at delivery: 56%) [19],[23],[36],[37]. The "WHO target" scenario modeled the current WHO goal that 80% of pregnant women be HIV-tested and 80% of HIV-infected women receive PMTCT services [20],[37]. The "optimal" uptake scenario simulated 95% uptake of the complete PMTCT cascade through delivery, likely representing the best practically achievable outcomes and lowest MTCT risks for the evaluated PMTCT regimens. A scenario of full, 100% uptake was also examined in sensitivity analyses (Tables D–G in Text S1), to represent the maximum potential biologic efficacy of each regimen.
Model Structure
Antenatal and intrapartum outcomes: MTCT model.
The MTCT model is a previously published, decision-analytic simulation of a cohort of pregnant women from the time of conception through delivery (TreeAgePro) [28],[29]. The model uses a decision-tree (deterministic) structure, including probabilities of the following: presentation to ANC; offer and acceptance of HIV testing; receipt of HIV test results; clinical assessment for ART eligibility; CD4 testing and receipt of results; offer of, acceptance of, and adherence to ARVs for PMTCT; maternal mortality during pregnancy; HIV testing in labor for women with unknown or negative HIV status; live birth; infant HIV infection by the time of delivery; and linkage to postnatal care and ART for mothers and infants (Figure A in Text S1).
Postnatal outcomes: CEPAC adult model.
The CEPAC model of adult HIV infection is a computer simulation model of HIV disease in adults. Technical details of the CEPAC model are described in Text S1 [30],[38]; outcomes of the CEPAC model for postpartum women have been validated against published data (Text S1) [32]. For this analysis, the adult CEPAC model was used only to project maternal mortality risks during the first 2 y after delivery, in order to inform infant mortality rates and duration of breastfeeding in the infant model.
Postnatal outcomes: CEPAC infant model.
A first-order, Monte Carlo simulation model of infant HIV infection and survival was added to the adult CEPAC model (Figure B in Text S1) [29]. Infants enter this model at birth and are assigned one of three HIV categories (HIV-unexposed, HIV-exposed but uninfected, or HIV-infected), as well as one of three maternal disease categories (HIV-uninfected, HIV-infected and "ART eligible," or HIV-infected and "non-ART-eligible"). Over the first 2 y of life, modeled infants face a monthly probability of four key clinical events: (1) incident maternal HIV infection during breastfeeding, if mother was previously uninfected, causing infants to transition from "unexposed" to "exposed, uninfected"; (2) maternal death, with risks derived from the adult CEPAC model as above, after which infants are no longer at risk for HIV infection but are at higher risk of death due to orphanhood [39]–[42]; (3) infant HIV infection through breastfeeding, if infant was previously uninfected; and (4) infant death from any cause. Risks of infant mortality are stratified by infant HIV exposure and infection status, by receipt of ART if infected, and by maternal vital status.
The MTCT and CEPAC models were linked to allow a combined analysis in which each woman–infant pair is simulated together from the time of first presentation at ANC through pregnancy and delivery (the MTCT model), and then each woman and infant are simulated separately through the first 2 y postpartum (the CEPAC models). Details of the linkages between the CEPAC and MTCT models have been published previously [29] and are further described in Figures A and B in Text S1.
Loss to follow-up.
During ANC in the MTCT model, women may be lost to follow-up between first ANC presentation and delivery [11],[24],[43]–[47], between delivery and 6 wk postpartum [11],[43],[44],[48]–[50], and after linkage to postnatal HIV care [43],[44],[51]–[56]. In the absence of data regarding rates of adherence to the Option A or Option B regimens during breastfeeding, the impacts of medication interruptions or discontinuations were assumed to be included in sensitivity analyses examining "highest risk" postnatal MTCT estimates.
Model Input Parameters
Baseline maternal characteristics reflected cohorts of pregnant women in Zimbabwe (Table 2). At first ANC visit, mean age was 24 y (SD: 5 y) [57], and the proportion with CD4≤350/µl was 36%, based on data from Zimbabwe [58]. In the base case, MTCT risks were derived as the average (mean or midpoint) of risks reported in PTMCT studies in Africa (Table 3; Text S1) [4]–[10],[12]–[15],[58]–[69]. To avoid underestimating early postpartum MTCT risks, we included only data from breastfed infants, necessarily excluding pivotal PMTCT studies among replacement-fed populations [8],[70]–. In the absence of reported postnatal transmission risks for infants older than 6 mo of age who continue to breastfeed with ongoing prophylaxis (Option A or B), we assumed a constant monthly risk based on data in younger children, as has been observed for postnatal transmission without prophylaxis [73]. Infant mortality rates (Table 4) were derived from Joint United Nations Programme on HIV/AIDS HIV-deleted mortality estimates (HIV-unexposed infants) [74], the ZVITAMBO study in Zimbabwe (HIV-exposed, uninfected infants) [75], and pooled analyses of several African cohorts (HIV-infected infants) [26],[76],[77].
Model Validation and Sensitivity Analyses
Validation of model-derived MTCT and mortality risks against published data, and sensitivity analyses on many clinical and programmatic parameters, have been reported previously [29].
For this analysis, in addition to the impact of PMTCT uptake and regimen examined in the base-case analyses, we conducted univariate sensitivity analyses on three key factors influencing transmission risk. First, to examine the impact of the range of published MTCT risks for each regimen, we defined "highest risk" and "lowest risk" scenarios. The "lowest risk" scenarios use the lowest published MTCT risks for each drug regimen, reflecting the best reported field effectiveness or trial efficacy, and likely representing the most adherent study populations; the "highest risk" scenarios use the highest published MTCT risks for each drug regimen. Second, because the proportion of women with CD4≤350/µl or WHO stage 3/4 disease at first ANC visit has been reported to range widely (23%–68% [78],[79]), we varied this proportion in sensitivity analyses from 0% to 100%. Third, we investigated the contribution of prolonged breastfeeding by projecting MTCT risk at 4–6 wk of age (primarily reflecting transmission that occurs in the absence of breastfeeding), as well as after 18 mo of breastfeeding (the median duration reported in a cohort from Zimbabwe [58]), with ARV prophylaxis continued throughout breastfeeding.
We identified the parameters that exerted the greatest impact on MTCT risks by comparing the range of MTCT risks projected when each parameter was varied through clinically plausible ranges; the largest range of projected MTCT risks reflected parameters with the greatest influence on model results. We then performed multivariate sensitivity analyses to determine combinations of these factors necessary to reach MTCT risks less than 5%.
To further examine the multiplicative impact of individual components of the PMTCT cascade, we varied uptake at each step in the care pathway (access to ANC, HIV testing in ANC, receipt of HIV test results, medication availability, adherence to medications, and linkage to postnatal HIV-related care), as well as the availability of CD4 counts and ART for women with CD4≤350/µl.
MTCT Risk among Infants Born to Women HIV-Infected Before Pregnancy (Cohort 1)
The modeled 12-mo MTCT risk in the sdNVP-based 2008 Zimbabwean National PMTCT Program was 20.3% (Table 5, top). Modeled improvements in PMTCT uptake in the 2009 National PMTCT Program are projected to have reduced this risk to 18.0%. If sdNVP could be replaced by WHO-recommended regimens at the current 56% uptake level, MTCT risk would be projected to fall to 14.4% with Option A, or 13.4% with Option B. The potential impacts of further improvements in coverage are highlighted in the "WHO target" and "optimal uptake" scenarios. If Option A were implemented at the WHO target level of 80%, MTCT risk would be projected to fall to 10.5%; "optimal" 95% uptake would reduce this further to 7.7%. With Option B, these risks are projected at 9.1% (80% uptake) and 6.1% (95% uptake). Similar impacts of PMTCT regimens and uptake scenarios are seen for the secondary outcomes of infant infection risk at 4–6 wk of age, 2-y pediatric survival, and 2-y pediatric HIV-free survival (Tables E–G in Text S1).
Population-Level Results for All Women Becoming Pregnant Each Year in Zimbabwe (Cohort 2)
For an annual pregnancy cohort in Zimbabwe, incorporating HIV-negative women, chronically HIV-infected women, and women with incident HIV infection (Table 5, bottom), the overall modeled 12-mo risk of infant HIV infection under the 2008 National PMTCT Program was 3.5%, representing 13,910 HIV-infected infants. Improvements in uptake are modeled to have reduced this risk to 3.2% (12,440 infections) by 2009, averting 1,470 infections. Replacement of sdNVP by Option A or B at the current uptake level would be projected to reduce this risk to 2.4%–2.6% (9,560–10,200 infections), and improved levels of uptake would reduce this modeled risk further, to 1.3% (4,950 infections, a 60% reduction in infant infections compared to sdNVP at 56% uptake) with Option B at "optimal" 95% uptake.
Univariate Sensitivity Analyses
Univariate sensitivity analyses investigating the individual impacts of PMTCT uptake, lowest/highest risk scenarios, maternal CD4 count, breastfeeding duration, and PMTCT regimen among Cohort 1 are shown in Figure 2. When individual parameters were varied from the base-case scenario (Option A regimen, 12 mo of breastfeeding, 36% of mothers ART-eligible, and average of published MTCT risks for each regimen), PMTCT uptake was the most influential single parameter (Figure 2, widest bar). Projected transmission, with all other parameters held equal, ranged from 6.2% (100% uptake), through 14.4% (56% uptake, indicated by "base-case projection line"), to 17.9% (36% uptake). The second most influential parameter was the range of published MTCT risks for each regimen (ranges shown in Table 3): with Option A at 56% uptake, 12-mo MTCT risks ranged from 8.8% ("lowest risk") to 18.5% ("highest risk"). The individual impacts of PMTCT uptake and lowest/highest risk scenarios, as well as of maternal CD4 count and breastfeeding duration, were greater than the impact of the choice of PMTCT regimen (Figure 2, narrowest bar). Additional univariate sensitivity analyses suggested that variations in the availability of HIV testing in labor and sdNVP for women identified as HIV-infected during labor also did not change the policy conclusions (Text S1). Overall, these univariate sensitivity analyses demonstrated that optimizing any single parameter shown in Figure 2 did not reduce modeled MTCT risk to less than 5%, underscoring the need for improvements in multiple parameters simultaneously to approach the "virtual elimination" of HIV in Zimbabwe.
Tornado diagram summarizing the results of key one-way sensitivity analyses. Model parameters are on the vertical axis. For each parameter, the value used in the base-case analysis is listed in parentheses, followed by the range examined in sensitivity analysis. For example, the "regimen" provided for PMTCT is varied from Option B (lowest MTCT risk with all other parameters held constant), through Option A (base-case MTCT risk), to sdNVP (highest MTCT risk). The horizontal axis represents projected MTCT risk by the time of weaning. The solid vertical line represents transmission risk (14.4%) at the base-case set of parameters: 56% uptake, mean published MTCT risks, 36% of mothers with CD4<350/µl, breastfeeding duration of 12 mo, and the WHO "Option A" regimen. The dashed vertical line represents the 5% MTCT target of "virtual elimination" expressed by international HIV/AIDS agencies including WHO and the Joint United Nations Programme on HIV/AIDS. ARV prophylaxis in the Option A and Option B regimens is assumed to continue throughout the duration of breastfeeding.
Multivariate Sensitivity Analyses
Multivariate sensitivity analyses highlighted the combinations of factors necessary to reduce MTCT among Cohort 1 to the WHO target of less than 5% (Figure 3, regions shaded in green). For example, at 80% uptake of Option A (middle panel), only if the lowest published MTCT risks and avoidance of breastfeeding were assumed was the <5% target projected to be achieved. With 80% uptake of Option B, a projected risk less than 5% still required assumption of the lowest published MTCT risks, but permitted breastfeeding durations up to 18 mo. With both the lowest published transmission risks and "optimal" (95%) uptake, 12-mo MTCT risks could decrease to 3.7% (Option A) or 1.9% (Option B).
Each horizontal block represents results for a specific drug regimen: sdNVP (top), Option A (middle), and Option B (bottom). Within each block, four levels of uptake are depicted across the top horizontal axis: 56% uptake (current estimated uptake in Zimbabwe), 80% uptake (the WHO target), 95% uptake (reported in neighboring Botswana), and 100% uptake (to reflect maximum biologic efficacy of each regimen). The vertical axis illustrates three durations of breastfeeding (BF) for each modeled PMTCT regimen: 18 mo (median in Zimbabwe), 12 mo (concordant with 2010 WHO infant feeding guidelines), and no breastfeeding; ARV prophylaxis in the Option A and Option B regimens is assumed to continue throughout the duration of breastfeeding. The lower horizontal axis shows three categories of published MTCT risks for each drug regimen, including the lowest published risks, the average of published risks (the base-case parameters), and the highest published risks. The percentage in each cell reflects the MTCT risk associated with each set of parameters, and cells are color-coded to reflect broad categories of transmission. Red-colored cells indicate MTCT risks>10%, yellow-colored cells indicate MTCT risks between 5% and 10%, and green-colored cells indicate MTCT risks<5%.
Impact of Overall Product of Participation (Cohort 1)
When overall uptake by the time of delivery was held constant at any given level, the specific step in the cascade at which uptake was varied did not affect 4–6-wk MTCT risk (Table 6). In contrast, the proportion of women–infant pairs linking to postnatal care had a substantial impact on 12-mo MTCT risk, especially with Options A and B (Table 7).
Impact of Available CD4 Counts and ART for Women with CD4≤350/µl (Cohort 1)
In the base-case analysis, CD4 assays were assumed to be available only in the Option A and Option B strategies; for sdNVP, ART eligibility was assessed clinically, with a sensitivity of 36% for WHO stage 3/4 disease or CD4≤350/µl [80]. Furthermore, the proportion of women offered medications was assumed to be equal among identified ART-eligible women (offered ART) and all others (offered the sdNVP, Option A, or Option B regimens). Two modeled scenarios demonstrated the impact of improvements in CD4 and ART availability. Table 8 (top) depicts a scenario in which no CD4 assays were available, regardless of regimen. At 56% uptake of sdNVP or Option A, although 36% of the cohort was truly ART-eligible, only 7% of HIV-infected women were identified as ART-eligible and received ART. Table 8 (bottom) shows a scenario in which CD4 assays were available for all women identified as HIV-infected in ANC, and all women with CD4 values≤350/µl were offered ART. At 56% uptake of sdNVP or Option A, this scenario of CD4/ART availability led 25% of women to be identified as ART-eligible and to receive ART. Although the proportion of women receiving sdNVP or antenatal ZDV decreased from 49% to 31% (to maintain a total uptake of 56%), MTCT risks at 4–6 wk were substantially lower when CD4 assays were available. Notably, in the sdNVP strategy at 56% uptake, adding CD4 assays and ART for eligible women reduced 4–6-wk MTCT from 13.8% to 11.4%, a larger impact than that of replacing sdNVP with Option A without CD4/ART availability (4–6-wk MTCT risk of 12.0%). Under the Option B strategy, the effect of targeting ART to women with low CD4 counts was markedly smaller: at 56% uptake of Option B, prioritizing ART for women with CD4 values≤350/µl would reduce 4–6-wk MTCT from 9.9% to only 9.6%, by slightly shifting the distribution of women on three-drug ARVs from non-ART-eligible to ART-eligible women.
We present results from a validated computer simulation model of MTCT in Zimbabwe, a setting where high HIV prevalence, prolonged breastfeeding, and limited resources make the WHO 2010 PMTCT guidelines both critical and challenging to implement. These analyses enumerate the potential benefits of improved PMTCT services along two dimensions: implementation of the WHO-recommended Option A or B regimens, and improved uptake of any given regimen at each step in the PMTCT cascade (Figure 1). Our results are similar to those from prior analyses using different modeling methodologies, including the analyses from which the initial targets were generated; consistent findings suggest that "virtual elimination" will require massive scale-up of PMTCT services [22],[81]. Although the WHO target may therefore seem difficult to reach, the WHO's "3 by 5" campaign (to deliver ART to 3 million HIV-infected patients by 2005) demonstrated the role that such ambitious public health goals can play in catalyzing efforts to dramatically expand HIV/AIDS services [82]. In addition, the analyses presented in this article simultaneously examine PMTCT uptake, breastfeeding duration, the range of MTCT risks published for each regimen, and both Options A and B from the 2010 WHO PMTCT guidelines, to identify combinations of factors that will facilitate achieving MTCT risks of less than 5% and the "virtual elimination" of pediatric HIV.
Most importantly, we find that improvements in PMTCT uptake are critical to approaching the goal of virtual elimination of MTCT. For example, a marked increase in PMTCT uptake occurred in Zimbabwe between 2008 (36%) and 2009 (56%), despite a period of economic hyperinflation [83]; as a result, projected MTCT risk was reduced from 20.3% to 18.0%, and an estimated 1,470 additional new infections were averted in a single year. Furthermore, once sdNVP is replaced by either WHO-recommended regimen, the level of PMTCT uptake exerts a far greater impact on MTCT rates than does the specific choice between Option A and Option B. Building from the 2009 National PMTCT Program in Zimbabwe, replacing sdNVP with Option A at 56% uptake (MTCT risk, 14.4%) would be more effective than expanding sdNVP uptake to 80% (MTCT risk, 15.4%). However, once the program reaches 56% uptake of Option A, improving uptake of Option A to 80% (MTCT risk, 10.5%) is projected to result in better outcomes than would replacing Option A with Option B at current uptake (MTCT risk, 13.4%). Notably, even with 95%–100% uptake, there are very few scenarios in which MTCT risk is estimated to fall below the 5% "virtual elimination" target threshold set by the WHO (Figure 3). With 12 mo of breastfeeding and average published MTCT risks for each regimen, nearly 100% uptake of Option B would be required to reach MTCT risks of less than 5%.
The results of this analysis depend critically on the modeled effectiveness of each ARV regimen, leading to two key conclusions. First, Option B may not be superior to Option A in preventing MTCT. The ranges of published MTCT risks for Options A and B are wide and overlapping (Table 3), and no randomized comparison of Option A with Option B has yet been reported. While data from available trials are limited by differences in populations and interventions [4]–[15],[67],[84], they suggest that Options A and B might have similar efficacy among women with CD4>350/µl, supporting WHO's equally strong recommendation of both regimens [21]. Results of a multi-national clinical trial comparing these regimens in women with CD4>350/µl will critically inform policy decisions around Options A and B [85].
Second, the lowest published MTCT risks for each regimen likely reflect an additional contribution of medication adherence, beyond that explicitly included in our MTCT model. For example, the lowest reported MTCT risks with maternal triple-drug ARV regimens in breastfeeding suggest 0% transmission by 6 mo of age, even among women with CD4<200/µl [9], which is lower than other reported risks of 0.5%–2.9% [6],[7],[10]–[13],[15]. Zero transmission was observed in a trial in which 92%–99% of women achieved viral suppression (HIV RNA<400 copies/ml) at delivery and 6 mo postpartum, suggesting that sustained adherence might have been greater in this trial than in trials reporting higher MTCT rates without such suppression data [9]. Among mother–infant pairs attempting to complete the Option A or Option B regimens beyond 6 mo of breastfeeding, adherence has not yet been reported. Based on high reported loss to follow-up rates among HIV-infected adults on ART, particularly postpartum women, as well as anecdotal evidence of the challenges of administering daily medications to otherwise healthy infants, it might be anticipated that the adherence that is observed when Options A and B are implemented in treatment programs will be lower than the trial-based adherence rates that are reflected in our base-case and "lowest risk" scenarios [43],[86].
In addition to the range of published MTCT risks for each regimen, reduced duration of breastfeeding is a key parameter that might permit the risk of MTCT to approach 5%. In settings where replacement feeding is the norm, MTCT risks have been reduced to 0%–2% [1],[2]. However, in Zimbabwe, as in many other resource-limited settings, infant formula milk may not be available, affordable, socially acceptable, or safe (due to lack of clean water or facilities for clean formula preparation) [3]. Replacement feeding, while reducing HIV transmission risk, therefore confers high risks of diarrheal disease, malnutrition, and mortality [3],[8]. Interventions to safely reduce breastfeeding duration in such settings, such as improved societal infrastructure for safe water systems, would likely confer tremendous health benefits, extending far beyond the infants of HIV-infected women, but will be costly and challenging to implement [87]. In the interim, our results suggest that promotion of high levels of access to postnatal care and adherence to ARV prophylaxis during breastfeeding will be critical to reduce the risk of MTCT to less than 5%.
Although PMTCT uptake in low- and middle-income countries has risen from 10% in 2004 to 53% in 2009 [19],[37], greater access to care and medications for HIV-infected pregnant women is still needed. The PMTCT "cascade" of care comprises multiple steps at which pregnant and breastfeeding women and their infants can be lost from care, and overall uptake is reduced multiplicatively at each step [22],[24],[25],[88]. For example, considering eight steps (access to ANC, HIV testing, receipt of test result, CD4 testing, receipt of CD4 result, adherence/retention before delivery, presentation to postnatal care, and adherence to breastfeeding prophylaxis regimens), each with the 92% average uptake observed in the PEARL multi-country study [24], the proportion of women completing care may be as low as 0.926 = 61% by delivery, or 0.928 = 51% by weaning. Notably, we find that the specific step in the antenatal PMTCT cascade at which improvements are made does not impact the risk of MTCT, if uptake is improved equally among ART-eligible and non-ART-eligible women. However, large reductions in the risk of MTCT are projected to occur if PMTCT uptake is increased by improving the proportion of ART-eligible women who receive ART (for example, through greater availability of CD4 testing and timely CD4 result return, or through selection of the Option B strategy). In addition, interventions to improve linkage to postnatal maternal HIV-related care (and ART for ART-eligible breastfeeding mothers) may substantially reduce postnatal HIV transmission. A focused operational research agenda is critical to identify, implement, and evaluate interventions that improve uptake and retention at each step in the PMTCT cascade, with a particular focus on availability of CD4 assays and ART for women with low CD4 counts [89].
There are three main limitations to this analysis. First, computer models simplify complex biologic and operational processes. Second, data from multiple sources were necessarily combined. However, sensitivity analyses were conducted to examine the effects of variation in key simplifying assumptions, including CD4 assay availability and the availability of HIV testing and sdNVP during labor, as well as wide ranges for each model input parameter. We found that these assumptions and data inputs had no substantive impact on policy conclusions, except where highlighted in the Results and Discussion. Finally, we report only short-term pediatric outcomes, and exclude potential impacts on maternal or community health resulting from expansion of PMTCT programs. In addition to a reduction in infant HIV infections, many other benefits may result from the planned transition from sdNVP to Option A or B, including the avoidance of exposure to sdNVP and the associated risk of drug-resistant virus for both mothers and infants [90],[91], as well as long-term maternal and pediatric health benefits associated with the monitoring and treatment infrastructure required for implementation of more complex PMTCT regimens. The potential health benefits and costs of these "indirect effects" will comprise important areas of future research.
In Zimbabwe, the planned implementation of the 2010 WHO PMTCT guidelines with Option A is projected to substantially reduce infant HIV infection risk compared to the 2009 national program. In order to approach the goal of "virtual elimination" of pediatric HIV (MTCT risk less than 5%), a national program based on either Option A or Option B will also need to include strategies to improve PMTCT uptake to nearly 100% throughout pregnancy and breastfeeding, to safely reduce the duration of breastfeeding, and to support medication adherence (thereby maximizing the effectiveness of each ARV regimen) during both pregnancy and breastfeeding.
Supporting Information
Text S1.
Additional information on methods and model structure.
The authors gratefully acknowledge Callie Scott, Jessica Becker, and Rodrigo Cerda for assistance with modeling analyses and manuscript preparation, and Batsirai Chikwinya, Agnes Mahomva, Rumbidzai Mugwagwa, Stanley Mashumba, and Charity Zvandaziva for critical interpretation of model results.
We are indebted to the entire CEPAC-International team and investigators for their contributions, including Christine Danel, Thérèse N'Dri-Yoman, Eugène Messou, Raoul Moh, Eric Ouattara, Catherine Seyler, and Siaka Touré (Programme PACCI, Abidjan, Côte d'Ivoire); Yazdan Yazdanpanah (Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, EA 2694, Faculté de Médecine de Lille, and Laboratoire de Recherches Économiques et Sociales, Centre National de la Recherche Scientifique Unité de Recherche Associée 362, Lille, France); Xavier Anglaret, Delphine Gabillard, and Hapsatou Touré (INSERM U897, ISPED, Université Bordeaux 2, Bordeaux, France); Nagalingeswaran Kumarasamy and A. K. Ganesh (Y.R. Gaitonde Centre for AIDS Research & Education, Chennai, India); Catherine Orrell and Robin Wood (University of Cape Town, Cape Town, South Africa); Neil Martinson and Lerato Mohapi (Perinatal HIV Research Unit, WITS Health Consortium, Johannesburg, South Africa); Kara Cotich, Sue J. Goldie, April D. Kimmel, Marc Lipsitch, Alethea McCormick, Chara Rydzak, George R. Seage III, and Milton C. Weinstein (Harvard School of Public Health, Boston, Massachusetts, US); C. Robert Horsburgh (Boston University School of Public Health, Boston, Massachusetts, US); Heather E. Hsu (Harvard Medical School, Boston, Massachusetts, US); Timothy Flanigan and Kenneth Mayer (Miriam Hospital, Providence, Rhode Island, US); A. David Paltiel (Yale University, New Haven, Connecticut, US); Aima Ahonkhai, Jason Andrews, Ingrid V. Bassett, Melissa A. Bender, Julie Levison, Benjamin P. Linas, Elena Losina, Zhigang Lu, Sarah Lorenzana, Bethany Morris, Mai Pho, Lynn Ramirez, Corina Rusu, Callie A. Scott, Caroline Sloan, Alexis Sypek, Lauren Uhler, Bingxia Wang, and Angela Wong (Massachusetts General Hospital, Boston, Massachusetts, US).
We are also indebted to the CEPAC-International Scientific Advisory Board, including Richard Chaisson, Victor De Gruttola, Joseph Eron, R. R. Gangakhedkar, Jonathan Kaplan, Salim Karim, Thérèse N'Dri Yoman, Douglas Owens, and John Wong.
This work was presented in part at the Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts, US; February 2011; Abstract #739.
Ethics: This work was approved by the Partners Healthcare IRB, Boston, Massachusetts, US.
Author Contributions
Conceived and designed the experiments: AC FP JK BE MM RW FD AM KF. Performed the experiments: AC JP JE AR. Contributed reagents/materials/analysis tools: AC RW KF. Wrote the first draft of the manuscript: AC. Contributed to the writing of the manuscript: AC FP JK JP BE MM RW FD JC AR AM KF. ICMJE criteria for authorship read and met: AC FP JK JP BE MM RW FD JC AR AM KF. Agree with manuscript results and conclusions: AC FP JK JP BE MM RW FD JC AR AM KF. Critical interpretation of model results: AC FP JK JP BE MM RW FD JC AR AM KF.
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text: France's most unpredictable filmmaker, the wonderful Alain Cavalier (Le combat dans l'île, Thérèse) teams up with an actor in every way his eccentric equal, Vincent Lindon, to create this sly, witty look at men, power and politics. Cavalier himself takes the part of an imaginary President of the Republic, searching for a Prime Minister, who turns out to be Lindon. The two develop a kind of filial relationship, complete with all the accompanying jealousies, competitiveness and affection. Shot, like all of Cavalier's recent works, with a handheld digital camera, Pater was largely a kind of "improvised adventure," as Cavalier described it; he would often come up with an idea or a few lines of dialog, and from there he and Lindon would invent each scene. The result is a film at once revealing, provocative, and consistently engaging—a cinematic game that asks the spectators to play along. Actor Vincent Lindon in person for both screenings.


text:
[Tour Information]
[For more information....]
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Greetings from Hafdís
Thank you for your inquiry
Wherever you stay, you can apply
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text:
ADDeRabbi, an orthodox rabbi who is an occasional commenter on this blog, gave links to several posts in which Proverbs 24:17-20 was cited in reference to the death of Bin Laden.(See his comments on the post below.) I took the trouble to look at the links; I was curious to see with whom I agreed. Of course, all the posters agreed that dancing in the streets, or shouting "USA, USA" was not appropriate behavior, except, perhaps, for amkha, who may be allowed their jubilation. At the very least, they agreed that dancing in the street was not the Jewish ideal.
The response that surprised me most was that of William Galston, a former advisor to President Clinton and a noted philosopher, He writes in TNR
How should we respond to the killing of Osama bin Laden? My first reaction was unbridled joy. As I was crawling into bed (too late) last night, I giddily allowed myself to sing, "Ding, dong, the wicked witch" from The Wizard of Oz.
But then
This morning I had second thoughts, not because I harbored any doubts about the justice of the deed or had changed my mind about its positive consequences for the United States and the world, but rather because educated congregants at my synagogue reminded me of the restraints my religion places on the satisfactions of vengeance. One quoted Proverbs 24:17—"Do not rejoice when your enemy falls, and let not your heart be glad when he stumbles, lest the Lord see it and be displeased ."
So, after going to bed, with visions of Margaret Hamilton and Osama bin Laden dancing in his head, Bill Galston, philosopher and ethicist, went to shul in the morning, and had to be reminded by "educated congregants" that one should not rejoice at the fall of one's enemy .
I think that Galston's story may be what Plato called, a "Noble Lie", a pedagogic whopper told for maximum rhetoric effect. It is hard for me to imagine him singing "Ding Dong, the Witch is Dead" at any time, much less having to be reminded in shul on a Monday morning that one's passions need to be restrained. And if he hadn't gone to shul? No, he was doubtlessly using considerably literary license to get a point across to the folks chanting, "USA, USA". He had to say, "Look, I am like you. I am not some wimpy bleeding heart. I also wanted to whoop it up. But after the initial rush – which in my case actually lasted only a few seconds - I knew that this was not the goal we should aspire for."
We are mortals, not machines. There is a sense in which it is "natural" to rejoice over the death of an enemy; it is probably programmed into our DNA through eons of evolution. But part of moral education is not only to tame what is natural, "to conquer our drives" but to try to extinguish some of them altogether . Often we fail; we are mortals. But the better our moral training , the less likely we are to fail.
Had Galston written everything that he writes, but added, "I was a bit embarrassed at the unbridled joy that I felt since I should have known better", then that would have been more appropriate. But that would have lessened the pedagogic value of the story for amkha (Hebrew for: "liberal hawk readers of TNR")
The Chabad rabbis, including Rabbi Shmuely Boteach, were a bit more morally blunt than Galston. They say that Torah commands us to hate wicked people. Really? I once bought a frum children's book in which the author said that "Hashem hates Amalek". I never will forget the look of shock on the faces of my kids when they heard the line. How can Hashem hate anything? they asked. (I threw away the book; maybe I should have burned it first.)
Their Torah preaches hatred; mine doesn't. But, you will say, that's what the Torah says. To that I answer, the Torah speaks in the language of men. It is never right to hate people. Hatred is a destructive emotion. Anger is a destructive emotion, even when it is righteous. (See the Rambam on this, who by the way, also speaks in the language of men occasionally.) We are commanded to pray that sins be removed from the world, not the sinners. Hatred is a natural emotion? So is lust. Ask Rabbi Boteach, who has written on the subject. And that makes it…what?
When I heard that Osama Bin Laden was dead, my immediate feeling was not of joy but of relief. But then I started to think about it. How was he killed? Was this simply an assassination? Were innocents killed? Was there a possibility of bringing him to trial? Will there be repercussions? Can we expect retaliations against US targets? Will this make life easier or harder for American interests in the Middle East? How will this play in the region? Was he taken out because he was a threat or because of the wounding of our national pride? Was this a revenge killing? How many tyrants will use the killing of Bin Laden to justify their own "war on terror"?
After thinking a few minutes, I was still gratified, especially because, according to initial reports, which I would like to believe, Bin Laden was not killed until he showed resistance, albeit without a weapon. I was gratified that, unlike the Israelis, the US soldiers were willing to take grave risks to ensure that collateral damage was held to a minimum. No 12 –ton bombs were dropped on the compound (had we done so, we would have been war criminals, even if the target was Bin Laden.) Sure, the official explanation for no bomb was that it was important to verify that we had killed Bin Laden. But the fact remains that enormous political and physical risks were taken; and the lives of some innocents, anyway, were spared. That sends a powerful message to many quarters (I hope Israel is one of them.) Still, this was not an act of justice; it was an act, I hope, to prevent further evil.
I shed no tears over the death of Bin Laden. He was a horrible man and a horrible Muslim. He was a mass murderer. His desecration of religion nauseated me as a religious man. But I would have preferred a trial. And if he was to die without trial, I would have preferred that it be at the hand of one of his own treacherous allies. Life is not a video game, or a revenge match. A criminal plotting a major crime has to be stopped. But what we should do, we should do – not out of hatred, not out of vengeance, not out of wounded pride – but in order to stop evil.
And we should do it with humility, regret, and with a heavy heart – and, preferably, through an international system, if possible.
Not like cowboys.


text:
This Dawn framing camera (FC) image of Vesta shows Rubria crater, which is the crater with the dark and bright material, that is offset from the center of the image. Rubria's bright material mostly crops out of the rim of the crater and slumps towards the center. In contrast, Rubria's dark material is located outside of the crater rim in long streaks, as well as cropping out of the rim of the crater and slumping towards its center. The longest dark material streak that is still connected to Rubria's rim is located on the top part of the rim. But it is possible that the other streaks to the top of the rim, the farthest of which is approximately 15 kilometers (9 miles) from the rim, may also be associated with Rubria crater. Rubria is one of the freshest looking, and consequently probably one of the youngest, craters in visible in this image.
This image is located in Vesta's Gegania quadrangle, just south of Vesta's equator. NASA's Dawn spacecraft obtained this image with its framing camera on Oct. 22, 2011. This image was taken through the camera's clear filter. The distance to the surface of Vesta is 700 kilometers (435 miles) and the image has a resolution of about 63 meters (207 feet) per pixel. This image was acquired during the HAMO (high-altitude mapping orbit) phase of the mission.
The Dawn mission to Vesta and Ceres is managed by NASA's Jet Propulsion Laboratory, a division of the California Institute of Technology in Pasadena, for NASA's Science Mission Directorate, Washington D.C. UCLA is responsible for overall Dawn mission science. The Dawn framing cameras have been developed and built under the leadership of the Max Planck Institute for Solar System Research, Katlenburg-Lindau, Germany, with significant contributions by DLR German Aerospace Center, Institute of Planetary Research, Berlin, and in coordination with the Institute of Computer and Communication Network Engineering, Braunschweig. The Framing Camera project is funded by the Max Planck Society, DLR, and NASA/JPL.
More information about the Dawn mission is online at http://www.nasa.gov/dawn and http://dawn.jpl.nasa.gov.